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On the TRAIL to successful cancer therapy? Predicting and counteracting resistance against TRAIL-based therapeutics

Oncogene volume 32, pages 1341–1350 (2013)Cite this article

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Abstract

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and agonistic antibodies against TRAIL death receptors (DR) kill tumor cells while causing virtually no damage to normal cells. Several novel drugs targeting TRAIL receptors are currently in clinical trials. However, TRAIL resistance is a common obstacle in TRAIL-based therapy and limits the efficiency of these drugs. In this review article we discuss different mechanisms of TRAIL resistance, and how they can be predicted and therapeutically circumvented. In addition, we provide a brief overview of all TRAIL-based clinical trials conducted so far. It is apparent that although the effects of TRAIL therapy are disappointingly modest overall, a small subset of patients responds very well to TRAIL. We argue that the true potential of targeting TRAIL DRs in cancer can only be reached when we find efficient ways to select for those patients that are most likely to benefit from the treatment. To achieve this, it is crucial to identify biomarkers that can help us predict TRAIL sensitivity.

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Acknowledgements

We apologize to the many investigators whose important works were not cited here owing to space limitations. This work was supported by NIH Grant CA124545 (A Thorburn, K Behbakht and H Ford), Department of Defense (DOD) postdoctoral fellowship BC093627 and Swedish Research Council postdoctoral fellowship 2009-618 (L Dimberg), DOD Ovarian Cancer Idea Award OC06143 (K Behbakht), and Department of Obstetrics and Gynecology Academic Enrichment Fund (AEF), University of Colorado-Denver Hospitals (C Anderson).

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Authors and Affiliations

  1. Department of Obstetrics and Gynecology, University of Colorado School of Medicine, Aurora, CO, USA

    L Y Dimberg, C K Anderson, K Behbakht & H L Ford

  2. Department of Medicine, University of Colorado School of Medicine, Aurora, CO, USA

    R Camidge

  3. Department of Pharmacology, University of Colorado School of Medicine, Aurora, CO, USA

    A Thorburn & H L Ford

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  1. L Y Dimberg
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  2. C K Anderson
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  3. R Camidge
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  4. K Behbakht
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  5. A Thorburn
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  6. H L Ford
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Correspondence to H L Ford.

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Competing interests

HL Ford, K Behbakht and A Thorburn hold a patent on the use of Six1 to identify TRAIL-sensitive tumor cells.

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Dimberg, L., Anderson, C., Camidge, R. et al. On the TRAIL to successful cancer therapy? Predicting and counteracting resistance against TRAIL-based therapeutics. Oncogene 32, 1341–1350 (2013). https://doi.org/10.1038/onc.2012.164

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  • DOI: https://doi.org/10.1038/onc.2012.164

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